E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Polycystic Ovarian Syndrome |
|
E.1.1.1 | Medical condition in easily understood language |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Hormonal diseases [C19] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065161 |
E.1.2 | Term | Polycystic ovarian syndrome |
E.1.2 | System Organ Class | 100000004872 |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate efficacy of two doses of ESN364 versus placebo when administered for 12 weeks to decrease total testosterone (TT) levels. |
|
E.2.2 | Secondary objectives of the trial |
• To evaluate effect of two doses of ESN364 versus placebo to decrease luteinizing hormone (LH), free and total testosterone (TT) at Week 6, Week 12 (end-of-treatment), and Week 18
• To evaluate effect of two doses of ESN364 versus placebo to change progesterone (P4) and estradiol levels (E2) at Week 6, Week 12 (end-of-treatment), and Week 18
• To evaluate effect of two doses of ESN364 versus placebo to change follicle stimulating hormone (FSH) levels and LH/FSH ratio at Week 6, Week 12 (end-of-treatment), and Week 18
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Pre-menopausal woman between 18 and 45 years inclusive at screening;
2) Diagnosed with PCOS according to the Rotterdam criteria with the following modification: biochemical hyperandrogenism is mandatory (TT >50 ng/dL [1.7 nmol/L] at screening and at least one of the following two other Rotterdam criteria are additionally required for diagnosis of PCOS:
• Oligomenorrhea (≤6 menses per year) or oligo-ovulation and/or
• Polycystic ovaries on ultrasound (≥12 antral follicles in at least one ovary or ovarian volume ≥10 cm3);
3) Normal thyroid function (thyroid stimulating hormone [TSH] compatible with normal thyroid function); mild hypothyroidy treated with stable hormone replacement therapy is allowed if TSH is normal;
4) FSH and E2 within normal limits as judged by the investigator
5) Normal prolactin (PRL) levels as judged by the investigator;;
6) 17-hydroxy-progesterone levels, compatible with normal 21-hydroxylase activity);(<200 ng/dL [<6.1 nmol/L]. In case of a sample taken in luteal phase levels < 286 ng/dL [<8.7 nmol/L] are acceptable.)
7) In good physical and mental health as determined on the basis of medical history and general physical examination performed at screening; hematology and chemistry parameters, heart rate (HR) and/or blood pressure, and electrocardiogram (ECG) within the reference range for the population studies, or showing no clinically relevant deviations, as judged by the investigator;
8) Has a negative (normal or atypical squamous cell of uncertain significance) cervical smear (Papanikolaou test [PAP], cytobrush or equivalent) within 36 months prior to screening;or at screening and available before randomization;
9) Negative urine test for selected drugs (amphetamines benzodiazepines, cannabinoids, cocaine, tetrahydrocannabinol, barbiturates or opiates) of abuse at screening and before first administration of study drug;
10) Negative pregnancy test at screening and before randomization; not have been pregnant within 6 months prior to screening;
Note: pregnancy testing will consist of a serum pregnancy test at screening and urine pregnancy tests at other visits.
11) Women of childbearing potential agrees not to get pregnant and willing to be abstinent or to use adequate highly effective contraception (failure rate less than 1% per year) during the trial and for at least 42 days after end of treatment;
The following non-hormonal contraceptive methods are defined as acceptable:
• Partner with a vasectomy performed at least 3 months prior to the study and with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate. (The vasectomized male partner should be the sole partner for that subject).
• True abstinence: When this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptom-thermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception)
• Hormone-free intrauterine device (copper intrauterine device) in combination with a condom
• The subject is homosexual/has no intercourse with the opposite sex
• Partner is using condoms in combination with spermicidal cream or gel
Women of childbearing potential are defined as any female who has experienced menarche and are not post-menopausal or permanently sterilized (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy);
12) Willing to adhere to the prohibitions and restrictions specified in the protocol;
13) Informed Consent Form (ICF) signed voluntarily before any study-related procedure is performed; indicating that the subject understands the purpose of and procedures required for the study and is willing to participate in the study.
|
|
E.4 | Principal exclusion criteria |
1) Evidence of diabetes diagnosed on any of the following World Health Organization (WHO) criteria:
- Fasting plasma glucose (FPG) ≥7.0 mmol/l (126 mg/dl) or,
- Glycated hemoglobin (HbA1c) ≥6.5% /48 mmol/mol or,
- Random plasma glucose ≥11.1 mmol/l (200 mg/dl) in the presence of classical diabetes symptoms;
2) Concomitant use of insulin sensitizers is not allowed, if taken, they should be stopped at screening;
3) Use of anti-androgens within 3 months prior to screening;
4) Have been treated within 3 months of screening with any of the following drugs: GnRH agonist/antagonist, selective estrogen receptor modulator (SERM), selective progesterone receptor modulator (SPRM), dienogest, danazol aromatase inhibitors, glucocorticoids, mineralocorticoids, androgens, and depot contraceptive preparations;
5) Treatment with hormonal contraceptives (oral, transdermal, coated intrauterine device) should be stopped 1 month prior to screening;
6) Has undergone bariatric surgery within 6 months prior to screening;
7) Has undergone ovarian surgery (drilling, wedge resection,…) within 6 months prior to screening;
8) Has undergone hysterectomy or bilateral oophorectomy or both;
9) Has Cushing’s syndrome;
10) Has a history of or currently ongoing pelvic inflammatory disease;
11) Has a known severe allergy, hypersensitivity, or intolerance to drugs in general, including the study drug and any of its excipients;
12) Has a history of or a currently ongoing malignant tumor (except for basal cell carcinoma of the skin that has been treated with no evidence of recurrence);
13) Has active liver disease or jaundice, or values of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >1.3 times the upper limit of normal ULN; or total bilirubin >1.3 times the (ULN); or creatinine >1.25 times the ULN at screening;
14) Has any psychological disorder according to criteria indicated in the Diagnostics and Statistical Manual of Mental Disorders, 4th edition within one year before screening. Such disorders include, but are not limited to, alcohol (more than 3 glasses of wine, beer, or equivalent/day) and substance abuse/dependence within 2 years prior to the initial study medication administration;
15) Hemoglobin level <10 g/dL;
16) Has symptoms of clinically relevant acute or chronic illness in the 3 months before the initial study administration;
17) Judged by investigator to be inappropriate to participate in this study based on findings on the ECG regarding rhythm or conduction. A first degree AV block will not be considered as a significant abnormality;
18) Had a significant blood loss (including blood donation [>500 mL]) or had a transfusion of any blood product within 12 weeks prior to the initial study medication administration;
19) Has a medical condition or chronic disease (including neurological [including cognitive], hepatic, renal, cardiovascular, gastrointestinal, pulmonary, or endocrine disease), or malignancy that could confound interpretation of the study outcome as judged by the investigator (e.g., a condition requiring chronic treatment with valproic acid);
20) Has a history of poor compliance in clinical research studies;
21) Concurrent participation or participation within 3 months prior to screening in a drug/device or biologic investigational research study;
22) Subject is the investigator oor any sub-investigator, research assistant, pharmacist, study coordinator, or other staff or relative thereof who is directly involved in the conduct of the study;
23) Has a positive hepatitis panel (including hepatitis B surface antigen [HBsAg] or anti-hepatitis C virus [HCV] antibodies) or positive human immunodeficiency virus (HIV) antibody at screening;
24) Presence or sequellae of gastrointestinal, liver, kidney or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs as judged by the investigator.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Change in TT levels from baseline to end-of-treatment Visit (Week 12)
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
• Changes in menstrual cycle as measured by frequency menses, spotting, inter-menstrual bleedings
• Change from baseline in the PCOSQ score (total and subcategories) at Week 6 and Week 12 (end-of-treatment)
• Change in sex hormone levels (LH, free and TT levels) from baseline to Week 6, Week 12 (end-of-treatment), and Week 18 (Follow-up)
• Change in sex hormone levels (P4, and E2 levels) from baseline to Week 6, Week 12 (end-of-treatment), and Week 18 (Follow-up)
• Change in sex hormone levels (FSH and LH/FSH ratio) from baseline to Week 6, Week 12 (end-of-treatment), and Week 18 (Follow-up)
• Change in TT levels from baseline to Week 9 (at trough PK levels)
• Change in endometrium thickness, ovarian volume, number of follicles (cysts), and dominant follicle development (Y/N) assessed by 2D transvaginal ultrasound from baseline to Week 6 and Week 12 (end-of-treatment)
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
|
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 12 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 7 |